Total Synthesis of the Broad-Spectrum Antibiotic Amycolamicin

Abstract

The total synthesis of the antibiotic amycolamicin with a hybrid molecular architecture composed of five ring systems, which exhibits potent antibacterial activity against a wide range of drug-resistant bacteria, has been achieved in a convergent manner. A protecting-group-free intramolecular Diels–Alder reaction of a hydroxy tetraenal intermediate promoted by two equivalents of Et2AlCl, which proceeds highly diastereoselectively via an endo-equatorial transition state, has been utilized to construct the trans-decalin moiety of the molecule. The full structure of amycolamicin was assembled by a completely stereoconvergent N-acylation of a northern N-glycoside unit (α-anomer/β-anomer = 1:1.1) with a southern β-keto thioester segment followed by installation of the central tetramic acid moiety.

Studies towards the Total Synthesis of Amycolamicin: A Chiral Auxiliary‐Based Diels‐Alder Approach towards the Decalin Core

“…In light of these findings, a chiral directing group appeared necessary to achieve high levels of stereoselectivity in the critical IMDA on the way to 2 . Contrary to Kuwahara's [12] and also Baran's [13] findings, we had not expected a dramatic change in the stereochemical outcome of the IMDA for substrates incorporating a free allylic hydroxy group, such as in dodecatetraenals 9 a or 9 b .…”

“…Our route towards acid 2 is robust and scalable and at this point has allowed us to prepare multiple 100 mg quantities of ester 38 (only part of which has been converted into acid 2 ). However, we do recognize that compared to Kuwahara's synthesis [12] of the related decalin 8 a , which formally can be converted into 11 in two steps, our route requires more steps, as no chiral auxiliary and associated manipulations are required in Kuwahara's case. It is important to note, however, that earlier studies by Marshall had revealed the formation of 1 : 1 mixtures of the (desired) endo ‐equatorial and endo ‐axial products in the IMDA of 7‐alkoxy‐2,8,10‐undecatrienals [22b] .…”

“…[16] Following PMB removal, glycosylation of the free C(4) hydroxy group with 4 and final TBS-removal would furnish 1. [17] Compared to the strategy outlined in Scheme 1, the order of extensions of the decalin core is reversed in the published total syntheses of 1, with those of Kuwahara [12] and Baran [13] featuring aldehyde 8 a and ketone 8 b (Figure 2), respectively, as the core building block for (1) glycosylation and (2) elaboration of the N-glycosylated tetramic acid moiety.…”

“…[5,7,10] The unprecedented and challenging molecular structure of amycolamicin (1) in combination with its biological activity make it an attractive target for total synthesis and subsequent structure-activity relationship (SAR) investigations. However, in spite of its intriguing attributes, the first total syntheses of 1 have been described in the literature only very recently by the groups of Li [11] and Kuwahara, [12] respectively. While this manuscript was in preparation, Baran and co-workers published a third synthesis of 1, [13] which is very similar to the one by Kuwahara.…”

Total Synthesis of Kibdelomycin

“…In stark contrast, when the TBS group was removed to deliver free allylic alcohol 22 , the same intramolecular DA reaction provided the desired product ( 23 ) as a single diastereomer in 51 % isolated yield (as confirmed through X‐ray crystallography [12] ). The chelation between the free hydroxyl group and Lewis acid is essential for the selectivity [5b] …”